The 2011 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science has been awarded to C. David Allis and Michael Grunstein. These two innovative scientists established the key molecular connections between histones, histone modifications and chromatin structure and their effect on the regulation of gene transcription.

Grunstein and Allis have been pioneers in documenting cause-and-effect relationships between chromosomal histone modifications and gene expression. The implications of this research are very broad, including emerging links to human biology and disease.

Lectures by the recipients and a Rosenstiel Award dinner will be held at Brandeis University on April 14, 2011.

Grunstein is a Professor of Biological Chemistry in the Geffen School of Medicine and the Molecular Biology Institute at UCLA. Beginning more than 20 years ago, his laboratory began to address the role of histones in gene regulation. These early studies indicated that nucleosomes could repress the function of the general transcription machinery inside living cells and that the sites of histone modification whose charge is altered by acetylation are required for gene activity.

A series of papers then described the specific role of histone modifications in transcriptional repression and in the formation of quiescent chromosomal regions by the formation of heterochromatin. Particular attention was focused on several lysines within the N-terminal “tails” of histones H3 and H4. Grunstein and colleagues showed that these lysines must remain positively charged for proper repression of genes located near yeast chromosome ends. Their experiments also showed that key proteins known to affect gene silencing are structural components of heterochromatin and interact in vitro with the same positively charged histone H3 and H4 N-terminal sequences.\

The results also provided a molecular understanding of how heterochromatin can cause epigenetic silencing of neighboring genes and more generally created a new paradigm for conceptualizing transcriptional regulation: Key proteins recognize and interact with histone N-termini. A last paper in this series had an additional far-reaching influence on the study of chromatin structure within living cells: It introduced the use of PCR in conjunction with chromatin immunoprecipitation assays. This strategy has had widespread application in tracking the interaction of proteins with DNA during replication, recombination and repair as well as transcription within living cells.

Allis is the Joy and Jack Fishman Professor and head of the Laboratory of Chromatin Biology at the Rockefeller University. Allis and his collaborators have focused since 1978 on biochemical studies characterizing histone tail modifications and their role in regulating gene activity. In 1996, the Allis laboratory made the groundbreaking observation that a histone acetyl transferase (HAT) from Tetrahymena was the homologue of a genetically defined transcriptional coactivator from yeast (Gcn5) and that the yeast Gcn5 protein also had intrinsic HAT activity.

This study immediately crystallized concepts about direct links between histone acetylation and transcriptional activation. It was followed by many reports from Allis and others showing histone acetylase and deacetylase activities for previously identified transcriptional coactivators and repressors, thus extending the key idea. Allis then provided in vivo genetic evidence that: i) yeast histones are physiological targets of GCN5; ii) that they are acetylated at specific residues; iii) that Gcn5 HAT activity targets promoter-proximal histones and is required for transcriptional activation; iv) and that histone acetylation by Gcn5 causes leads to, rather than responds to, transcription.

Beyond these critical and numerous histone acetylation studies, Allis and colleagues further showed that the phosphorylation of an invariant H3 serine was functionally linked both to mitosis as well as to the mitogen-stimulation of gene activity and that specific evolutionarily conserved kinases are involved. They also made the important observation that specific phosphorylation events on serine and threonine residues could enhance specific acetylation events at adjacent lysines, indicating the importance of crosstalk between different histone modifications. In this context, Allis and colleagues discovered a long-sought role for the ubiquitylation of histones 2A and 2B and demonstrated a role for H2B lysine-ubiquitylation in transcription regulation-relevant methylation events on histone H3.

More recently, Allis and his collaborators have shown links between histone-specific methylation events and either heterochromatization/gene silencing or gene activation, depending on the precise lysine residue that is methylated and the extent of modification. This has stimulated a flood of studies from many laboratories on different histone methyltransferases and their corresponding complexes, similar to the different histone acetyltransferases and deacetylases identified by both the Grunstein and Allis laboratories. These studies have also led to many important regulatory proteins, which bind to acetylated and methylated histone sites and impact gene expression.

In sum, Grunstein and Allis have been pioneers in documenting cause-and-effect relationships between chromosomal histone modifications and gene expression. The implications of this research are very broad, including emerging links to human biology and disease.

Lectures by the recipients and a Rosenstiel Award dinner will be held at Brandeis University on April 14, 2011.

This is the 40th Rosenstiel Award. Recent previous awardees include Jules Hoffman and Ruslan Medzhitov for their pioneering studies of innate immunity (2010) and John Gurdon, Irving Weissman and Shinya Yamanaka for their work on reprogramming differentiated cells into stem cells (2009). View a list of all the past winners.